Currently, FDA approved clinical applications of 9-Tetrahydrocannabinol (THC) include control of nausea and vomiting associated with chemotherapy and for appetite stimulation for AIDS patients suffering from anorexia and wasting syndrome. However, THC also has significant potential in the treatment of glaucoma, the second largest cause of blindness, by decreasing intraocular pressure and by acting as a retinal neuroprotectant, through an interaction with the cannabinoid receptors expressed on the ocular tissues. To date, however, lack of an appropriate mechanism for effective topical delivery of THC has been a limiting factor. We propose to broaden the paradigm of THC research to appropriate drug design and delivery strategies to enhance ocular bioavailability, through topical administration, of this valuable medicinal compound. This project will test the hypothesis that selected novel hydrophilic amino acid (AA), dicarboxylic acid (DCA) or combination (AA-AA, AA-DCA) based THC prodrugs will improve transcorneal penetration and will demonstrate optimal resistance to enzymatic and chemical hydrolysis. Our approach in Aim 1 will be to select and synthesize THC prodrugs and their salts. Specifically, amino and/or dicarboxylic acids will be linked to THC in a manner to yield THC prodrugs (THC-AA, THC-AA-AA, THC-DCA, and THC-AA-DCA) representing a variety of computed logP values, charge and chain length and their salts. The identity of the prodrugs synthesized will be established using analytical tools such as HPLC-MS and NMR (1H and 13C). Under Aim 2, physicochemical characteristics, aqueous solubility, pH dependent solubility and stability in aqueous solutions, as well as bioreversion of the prodrugs in ocular tissue homogenates and aqueous and vitreous humor will be determined. In vitro permeability will be evaluated using isolated rabbit corneas. Finally, Aim 3 will determine ocular bioavailability and pharmacological activity of selected THC prodrugs in vivo in New Zealand albino rabbits. Intraocular pressure (IOP) lowering properties of the selected prodrugs will be compared to that of the parent drug, THC. Suitable formulations for topical delivery will be prepared. In addition to evaluating the effect on the IOP, ocular bioavailability of the most effective prodrug/dose will be determined in the anesthetized rabbit model using a dual probe ocular microdialysis technique to sample the aqueous and vitreous humor. Plasma THC levels, as well as THC acid and 11-hydroxy THC metabolite levels, at the final time point, will also be determined in these studies to estimate systemic exposure. It is expected that the innovative THC prodrugs proposed in this application will be markedly more hydrophilic and stable, compared to THC, and will show significant IOP lowering activity following topical application. Additionally, this study will provide a better understanding of the physicochemical and formulation characteristics necessary for drug penetration into the back-of-the eye tissues following topical administration and thus help improve treatment options for glaucoma as well as a host of other ocular diseases. PUBLIC HEALTH RELEVANCE: This STTR Phase I application is directed towards the development of hydrophilic tetrahydrocannabinol (THC) prodrugs for topical administration as eyedrops. Such prodrugs will be of great value in the prevention of loss or deterioration of vision in patients suffering from glaucoma.